Homer Isoforms Differentially Regulate Cocaine-Induced Neuroplasticity

• DOI: 10.1038/sj.npp.1300890
• Publication Date: 2005-09-15T02:28:45Z
• Authors: Karen K Szumlinski; Kenneth E Abernathy; Erik B Oleson; Matthias Klugmann; Kevin D Lominac; Dao-Yao He; Dorit Ron; Matthew During; Peter W Kalivas
• Keywords: Male; 0301 basic medicine; Neuronal Plasticity; Behavior, Animal; Dopamine; Microdialysis; Glutamic Acid; Motor Activity; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; Cocaine-Related Disorders; Mice; 03 medical and health sciences; Cocaine; Gene Expression Regulation; Homer Scaffolding Proteins; Animals; Protein Isoforms; Anesthetics, Local; Carrier Proteins; Chromatography, High Pressure Liquid

Homer proteins modulate neuroplasticity in excitatory synapses and are dynamically regulated by cocaine. Whereas acute cocaine elevates immediate-early gene (short) isoforms of Homer1 in the nucleus accumbens, withdrawal from repeated cocaine administration downregulates the expression of constitutive Homer1 isoforms. The present study determined whether or not this downregulation in constitutive Homer expression in the accumbens is necessary for enduring alterations in cocaine-induced changes in the brain and behavior. The long vs short Homer isoforms were overexpressed in the rat nucleus accumbens during drug abstinence, and the adaptations elicited by repeated cocaine on glutamate transmission and motor behavior were measured. It was found that both chronic and acute overexpression of constitutive, but not short, Homer isoforms abolished cocaine-induced sensitization of locomotor hyperactivity and prevented the development of glutamate abnormalities in the accumbens, including the reduction in basal extracellular glutamate content and the sensitized glutamate response to a subsequent cocaine challenge injection. Together, these data indicate that the enduring reduction of long Homer isoforms in the nucleus accumbens of cocaine-withdrawn rats is necessary for the expression of cocaine-induced neuroplasticity.